Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
1996-07-22
2001-04-03
Shaver, Paul F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S413000, C556S418000, C556S419000, C556S426000, C556S411000, C514S064000, C514S844000, C514S944000, C424S401000, C424S457000, C424S078030
Reexamination Certificate
active
06211393
ABSTRACT:
SUMMARY
Compound with silicon with the general formula:
in which
A, B, C, D are radicals different from OH linked to Si by covalent bonds,
two or three of these bonds with Si are bonds of Si—O—C Si—S—C or Si—N—C type, hydrolysable in vivo with formation of Si—OH bonds biologically active, especially when in contact with living tissues, the links A and D of the formula b) always being hydrolysable.
at least one of the hydrolysable bonds corresponds to an acyloxy, aryloxy or vinyloxy radical
at least one of the compounds obtained after hydrolysis of the said hydrolysable bonds is a stabilizer, and
the non hydrolysable links are of Si—C type and correspond to hydrocarbon or fluorocarbon radicals for which Si is not directly bound to a phenyl ring.
TECHNICAL FIELD
The present invention concerns compounds with biologically active silicon, especially when in contact with alive tissues, as well as the therapeutic and cosmetic applications of these compounds.
STATE OF TECHNIQUE
Silicon is a very common element in nature and is generally known under its natural inorganic forms such as silica and silicate, and also under the form of synthetic polymers, the silicones. These silicon compounds are barely soluble or not at all soluble in aqueous medium which explains their weak incidence at the alive organisms level. The silicones, in particular, are characterized by a great inertia towards the biological medium and consequently present a high biocompatibility.
However, the silicon, even in minute quantities, plays an important biological role and must be considered as an essential element of life. It is especially necessary for a normal growth of numerous species. It has been demonstrated that silicon was intervening in the connective tissues structuration in interacting with the glycosaminoglycan and proteins. This is one of the constitutive elements of proteins-glycosaminoglycan complexes found in the extracellular matrix of these tissues. Silicon also interacts with the glycosaminoglycan in the cartilage tissue development. We also know that silicon plays an important role in the bone formation where it favours the mineralization process.
Besides, silicon can be considered as a collagen constituent and we think that it plays a major role in the reticulation process of collagen fibres.
Silicon is also involved in the cell metabolism and it would be especially favourable to the metabolic activity of osteoblasts.
Beyond the cross-linking power of silicon and its implication in the metabolic activity of some cells, it appears that a high silicon content, in the tissues, jointly with the glycosaminoglycan content is characteristic of healthy and metabolically active tissues.
Today's researches tend to reinforce the idea that silicon intervenes in numerous biological mechanisms. Recent works have even demonstrated that silicon plays a major role, in the aluminium elimination by biological systems.
Works of the applicant have demonstrated that silicon compounds could constitute a form of assimilable silicon by the organism (as opposed to mineral silicon or to silicones) on condition that it possesses the characteristic of existing in aqueous solution under the form of soluble oligomers of low molecular weight. Furthermore, another necessary characteristic of the oligomers activity in aqueous solution is to present numerous Si—OH functions. So, it is obvious that the biological properties of these assimilable compounds by the organism, are only observed if they form soluble oligomers in aqueous solution, which result from a chain of siloxane bonds Si—O—Si, rich in Si—OH functions.
Apart from the fact that the presence of Si—OH highly polar functions, confers their water solubility to the oligomers, at the present time, we think that a part of the properties observed are conducted by the fact that the chemical species involved in most of the above mentioned biological mechanisms would be a form of silicon, the silicic acid, of Si (OH)
4
formula. This compound only exists in very low concentrations in water since it has a very strong tendency to polycondense to form silica.
Consequently we have researched more stable products similar to silicic acid, by chemically modifying the Si—OH functions. It quickly became obvious that these functions were essential for the biological activity. In other respects, we knew that a series of natural compounds, and among them, the tannins and the catecholamines were able of forming a complex with the silicic acid and like this were able of increasing its stability in solution. These complexes would be the way of transport for the silicic acid in the organism and it is under this form that the cell would introduce the silicon. Nevertheless, their stability is still too weak for the carrying out of a pharmacologically active product.
SUMMARY OF THE INVENTION
That is why the main object of the invention is to provide compounds with silicon possessing biologically hydrolysable links especially when in contact with living tissues and that will allow one to obtain oligomers possessing the biologically active Si—OH functions.
A compound that meets this requirement has the general formula:
in which
A, B ,C, D are radicals different from OH linked to Si by covalent bonds,
two or three of these bonds with Si are bonds of the Si—O—C—, Si—S—C or Si—N—C type, hydrolysable in vivo with the formation of biologically active Si—OH bonds especially when in contact with living tissues, the links A and D of the formula b) always being hydrolysable,
at least one of the hydrolysable bonds corresponds to an acyloxy, aryloxy or vinyloxy radical
at least one of the compound, obtained after hydrolysis of the said hydrolysable functions is a stabilizer
the non hydrolysable functions are of the Si—C type and correspond to hydrocarbon or fluorocarbon radicals for which Si, is not directly linked to a phenyl ring.
DESCRIPTION OF THE INVENTION
In the compound of the invention as above defined, the radicals which are hydrolysable biologically are consequently radicals linked to Si by an oxygen atom, a nitrogen atom or a sulphur atom. When a silicon atom is directly bound to an oxygen atom, these radicals are preferably acyloxy radicals or aryloxy radicals (such as phenoxy radicals) or even vinyloxy radicals. This preference can be explained by the fact that it is necessary to obtain the release of at least one stabilizer after the hydrolysable bonds hydrolysis. The best stabilizers are the carboxylic acids resulting from the acyloxy radicals hydrolysis, the phenol resulting from the aryloxy radicals hydrolysis and the enol resulting from the vinyloxy radicals hydrolysis.
When the silicon is linked by a sulphur atom, the hydrolysable radicals are preferably thioester or aryl or alkylthioether radicals.
When the silicon is linked by a nitrogen atom, the hydrolysable radicals are preferably amines, mono or disubstituted by hydrocarbon chains substituted or not by one or several functional groups, or by aryl or alkylamides.
The radicals linked to Si and which are not hydrolysable are those presenting a Si—C bond and they can be hydrocarbon radicals such as alkyl radicals, alkenyl, arylalkyl and aryl however excluding phenyl type of aryl radicals. This exclusion is justified by the fact that the phenyl-Si—OH type compounds obtained after hydrolysis of hydrolysable links, present negative effects on live organisms and are especially toxic in regard to liver, pancreas, bone marrow and the heart muscle (see the article “Bioactive silane and siloxanes” by R. R. Le Vier in the Chemical Bulletin, March 1986, pages 89-91). The non hydrolysable radicals can also be fluoroalkyl or fluoroalkenyl types of fluorocarbon radicals.
We shall notice that all the other types of biologically non hydrolysable bonds are excluded and especially the Si—O—Si bonds known for their chemical inertia and their absence of reactivity in regard to biological mediums.
Examples of compounds according to the invention are given here below:
Salicylic Alcohol Derivatives (or 2-hydroxybenzylalchohol):
2-oxo-benzyloxy-ethoxyme
Franco Andre
Gueyne Jean
Nicolay Jean-Francois
Seguin Marie Christine
EXSYMOL S.A.M.
Lydon James C.
Shaver Paul F.
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